Differences in Cell Cycle Status Underlie Transcriptional Heterogeneity in the HSC Compartment

Felicia Kathrine Bratt Lauridsen, Tanja Lyholm Jensen, Nicolas Rapin, Derya Aslan, Anna Sofia Wilhelmson, Sachin Pundhir, Matilda Rehn, Franziska Paul, Amir Giladi, Marie Sigurd Hasemann, Palle Serup, Ido Amit, Bo Torben Porse

Research output: Contribution to journalArticlepeer-review


Hematopoietic stem cells (HSCs) are considered a heterogeneous cell population. To further resolve the HSC compartment, we characterized a retinoic acid (RA) reporter mouse line. Sub-fractionation of the HSC compartment in RA-CFP reporter mice demonstrated that RA-CFP-dim HSCs were largely non-proliferative and displayed superior engraftment potential in comparison with RA-CFP-bright HSCs. Gene expression analysis demonstrated higher expression of RA-target genes in RA-CFP-dim HSCs, in contrast to the RA-CFP reporter expression, but both RA-CFP-dim and RA-CFP-bright HSCs responded efficiently to RA in vitro. Single-cell RNA sequencing (RNA-seq) of > 1,200 HSCs showed that differences in cell cycle activity constituted the main driver of transcriptional heterogeneity in HSCs. Moreover, further analysis of the single-cell RNA-seq data revealed that stochastic low-level expression of distinct lineage-affiliated transcriptional programs is a common feature of HSCs. Collectively, this work demonstrates the utility of the RA-CFP reporter line as a tool for the isolation of superior HSCs.

Original languageEnglish
Pages (from-to)766-780
Number of pages15
JournalCell Reports
Issue number3
StatePublished - 17 Jul 2018


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